1. Preventing Psychotic Disorders by Early Detection and Intervention William R. McFarlane, M.D. Maine Medical Center Research Institute Portland, Maine USA Tufts University School of Medicine

2. Disclosure: I am the owner of the PIER Training Institute, which provides training on request to public and not-for-profit mental health services.

3. Early detection and prevention in another illness “If you catch cancer at Stage 1 or 2, almost everybody lives. If you catch it at Stage 3 or 4, almost everybody dies. We know from cervical cancer that by screening you can reduce cancer up to 70 percent. We’re just not spending enough of our resources working to find markers for early detection.” ---Lee Hartwell, MD Nobel Laureate, Medicine President and Director, Hutchinson Center New York Times Magazine December 4, 2005, p. 56

4. Early detection and prevention in psychotic illness “The psychiatrist sees too many end states and deals professionally with too few of the pre-psychotic.” --Harry Stack Sullivan, 1927

5. Shortened productive lives Source: Mental Health Report of the Surgeon General

6. 75% Proportion of people who have one psychotic episode and schizophrenia and then develop disability

7. 2-3% Proportion of youth who develop schizophrenia or a severe, psychotic mood disorder

8. 12-15% Proportion of people with schizophrenia or a psychotic mood disorder who commit suicide

9. >33 : 1 Odds that a person with vs. without psychotic symptoms will attempt or commit suicide

10. 25 Years of life lost by people with schizophrenia due to all causes, including heart disease, cancer and suicide

11. Functioning as an effect of number of psychotic episodes

12. Age of onset of disabling mental illnesses

13. Age of onset of psychosis, Portland and Rest of Maine Cases ages 12-25

14. Biosocial theory Major psychiatric disorders are determined by the continual interaction of specific biological dysfunctions and specific social phenomena Psychological factors determine course at the case level by influencing biological and social forces

15. Cognitive Deficits Affective Sx: Depression Social Isolation School Failure Biological Vulnerability: CASIS Brain Abnormalities Structural Biochemical Functional Disability Social and Environmental Triggers Increasing Positive symptoms Early Insults e.g. Disease Genes, Possibly Viral Infections, Environmental Toxins After Cornblatt, et al., 2005

16. Biologic risk factors Genetic risk –80-85% heritability Non-genetic biologic risk –Prenatal infections (influenza) –Prenatal toxic exposure (lead) –Obstetrical complications –Traumatic (head trauma, perinatal period to adolescence) –Autoimmune (Rh incompatibility, increasing risk with multiple births) –Nutrition (starvation, vitamin D and omega-3 deficiency) –Heavy cannabis, other psychotogenic drug exposure Non-heritable genetic risk –Age of father >50; probably natural mutations in spermatogenesis –Spontaneous mutations in embryo after conception

17. Cortical volume reduction in childhood-onset schizophrenia, ages 14-19

18. Effects of genetic risk and family functioning on eventual schizophrenia-spectrum disorders * p < 0.001 **p = 0.582 G X E interaction: p=0.018 Tienari, Wynne, et al, BJM, 2004

19. Early prodrome Illusions Dread Insomnia Anorexia Social deficits Social & performance deficits Perceptual distortions Pervasive anxiety Withdrawal "Oddness" Functional deterioration Panic Misattribution High EE Late prodrome Psychosis Acute onset Biosocial causal interactions in schizophrenic prodrome Critical comments CD, EOI Anxiety Structural Family/Social Physiological

20. Is early intervention indicated prevention of psychotic disorders?

21. Risk of psychosis over 10 years Fusar-poli, et al, 2013

22. Trials of Indicated Prevention Buckingham, UK OPUS, Denmark PIER, Maine EDIPPP, USA GRN PACE I, II, Australia EDIE I, II, III, UK Addington, Canada PRIME, North America Omega-3 FAs, Austria Family psychoeducation Cognitive therapy Biological treatment

23. Early intervention is prevention One year rates for conversion to psychosis % 23.0% Fusar-Poli, et al, JAMA Psychiatry, 2013 Risk reduction = 66% 7.6%

24. Meta-analyses of RCTs Conversion to psychosis Study Fusar-poli, et al, 2013 van der Gaag, et al, 2013 Stafford, et al, 2013 Integrated treatment (Nordentoft, 2006, Bechdolf, 2012, McFarlane, 2014) Risk ratio (risk reduction) 0.34 (-66%; n=554) 0.46 (-54%) 0.54 (-46%; n=1246) 0.19 (-81%)

25. Portland Identification and Early Referral (PIER) Reducing the incidence of major psychotic disorders in a defined population, by early detection and treatment: Indicated prevention

26. Family practitioners Pediatricians General Public Mental health clinicians Military bases and recruiters Clergy Emergency and crisis services College health services PIER Team Advertising School teachers, guidance counselors, nurses, social workers Employers

27. Family practitioners Pediatricians School guidance counselors, nurses, social workers Employers General Public Mental health clinicians Military bases and recruiters Clergy Emergency and crisis services College health services PIER Team

28. Assessing Risk for Psychosis

29. Signs of prodromal psychosis Schedule of Prodromal Syndrome (SOPS), McGlashan, et al A clustering of the following: Changes in behavior, thoughts and emotions, with preservation of insight, such as: Heightened perceptual sensitivity To light, noise, touch, interpersonal distance Magical thinking Derealization, depersonalization, grandiose ideas, child-like logic Unusual perceptual experiences “Presence”, imaginary friends, fleeting apparitions, odd sounds Unusual fears Avoidance of bodily harm, fear of assault (cf. social phobia) Disorganized or digressive speech Receptive and expressive aphasia Uncharacteristic, peculiar behavior Satanic preoccupations, unpredictability, bizarre appearance Reduced emotional or social responsiveness “Depression”, alogia, anergia, mild dementia

30. Signs of prodromal psychosis Changes in behavior, thoughts and emotions, with preservation of insight, such as: Unusual perceptual experiences “Presence”, shadows, visual trails, ghosts Imaginary friends Fleeting apparitions Odd sounds Somatic illusions or hallucinations Heightened or dulled perceptions Vivid sensory experiences Sensations and thoughts located outside the body Frequent distortions or illusions Brief but frank hallucinations, minimal effect on behavior or thinking

31. Signs of prodromal psychosis Changes in behavior, thoughts and emotions, with preservation of insight, such as: Unusual fears Marked guardedness, distrustful Fear of assault (not social phobia) Avoidance of bodily harm Somatic delusions Severe nihilism Persistent persecutory self-referential thoughts Paranoia Extreme guilt, fear of harming others Bizarre obsessional preoccupations Fears of mind-reading Frank delusions, without full conviction

32. Signs of prodromal psychosis 2. Significant deterioration in functioning –Unexplained decrease in work or school performance –Decreased concentration and motivation –Decrease in personal hygiene –Decrease in the ability to cope with life events and stressors 3. Social withdrawal –Loss of interest in friends, extracurricular sports/hobbies –Increasing sense of disconnection, alienation –Family alienation, resentment, increasing hostility, paranoia

33. Intervening to Prevent Onset

34. Family-aided Assertive Community Treatment (FACT): Clinical and functional intervention Rapid, crisis-oriented initiation of treatment Psychoeducational multifamily groups Case management using key Assertive Community Treatment methods –Integrated, multidisciplinary team; outreach PRN; rapid response; continuous case review Supported employment and education –Collaboration with schools, colleges and employers

35. Family-aided Assertive Community Treatment (FACT): Clinical and functional intervention Cognitive assessments used in school or job Low-dose atypical antipsychotic medication –aripiprazole 2-20 mg, quetiapine 300-600 mg, risperidone 0.25-3 mg Mood stabilizers, as indicated by symptoms: –Mood stabilizing drugs: lamotrigine 50-150 mg, valproate 500- 1500 mg, low-dose lithium by blood level SSRIs, with caution, especially with aripiprazole and/or a family history of manic episodes

36. Key clinical strategies in family intervention specific to prodromal psychosis Strengthening relationships and creating an optimal, protective home environment: –Reducing intensity, anxiety and over-involvement –Preventing onset of negativity and criticism –Adjusting expectations and performance demands –Minimizing internal family stressors Marital stress Sibling hostility Confusion and disagreement –Buffering external stressors Academic and employment stress Social rejection at school or work Cultural taboos Entertainment stress Romantic and sexual complications

37. Outcomes

38. Efficiency of identification: Diagnosis for those eligible by geography and age n = 780 Referred for another disorder31440.2% Prodromal14819.0% Psychosis7910.1% Any psychiatric illness58969.4%

39. Treated cases converting to psychosis within 24 months (n = 148) Cases not converted121 81.8% Cases converted, 1-30 days 14 9.4% SOPS psychosis conversions 13 8.8%

40. First hospitalizations for psychosis Greater Portland vs. Maine Urban controls areas *p<0.0001

41. Ratio of PIER area to Urban Control area First hospitalizations for psychosis/100,000

42. PIER long-term outcome 4-12 years after identification of risk During 2-year treatment, 2001-2009 Received any treatment139100% Severe episode1410% Post-2-year treatment, 2-10 years Followed-up7252% Severe psychosis or hospitalization 913% In school or working5576%

43. Early Detection and Intervention for the Prevention of Psychosis (EDIPPP) A national multisite effectiveness trial of indicated prevention Reducing the incidence of major psychotic disorders in a defined population, by early detection and treatment: Indicated prevention

44. Early Detection and Intervention for the Prevention of Psychosis Effectiveness Trial at six sites: –Portland, Maine / Maine Medical Center –Glen Oaks, New York / Albert Einstein College of Medicine –Ann Arbor, Michigan / University of Michigan –Salem, Oregon / Oregon Health Sciences University –Sacramento, California / University of California at Davis –Albuquerque, New Mexico / University of New Mexico Sponsored by RWJF Risk-based allocation and incidence reduction Regression discontinuity and time series analyses Large and diverse nationally representative sample PIER community outreach and identification systems For further information: www.ChangeMyMind.org

45. Number of outreach activities and referrals within catchment areas during two years, by town or by zip code) Oregon One dot = one event Year 2 (3/09-3/10) Catchment Areas Outreach Activities Referrals

46. Entry and assignment criteria Ages 12-25 Living in the experimental catchment area Positive symptom score by SIPS criteria : –Clinical Low Risk (CLR) Control Sum <7; OR –Clinical High-Risk (CHR) Treatment Sum = 7 or more; OR –Early First Episode Psychosis (EFEP) Treatment Any 6 for < 1 month IQ 70 or higher No previous psychosis Not toxic or medical psychosis

47. Outcomes

48. Early identification across sites SITE Population Age-corrected rate**, at 25/100,000* Years of community outreach Maine 323,105 63%8 Michigan 344,791 37% Oregon 631,853 29%2.5 California 466,488 26% New York 557,725 17% 1.5 New Mexico 662,564 12% Total 2,986,526 27% ** Proportion (69.2%) of ages 12-35 population represented by ages 12-25 population *Rate for Nottingham, U.K., in Kirkbride, et al., Arch Gen Psychiatry. 2006;63:250-258

49. Demographic and Psychosocial Characteristics

50. Clinical Characteristics Current SCID-IV Axis-I Diagnoses Total (n = 337) Clinical Low- Risk (CLR) (n = 87) Treatment (High-Risk) (n = 250) p Clinical High Risk (CHR) (n = 205) Early First Episode (EFEP) (n = 45) No Diagnosis 14% 22% 14% 0%<.01 Mood Disorder42% 37%49% 18%<.01 (1) Bipolar16 (5%)2 (2%)12 (6%)3 (7%).38 (2) Major Depression114 (34%)27 (31%)83 (41%)3 (7%)<.01 Substance Abuse28 (8%)8 (9%) 7% 5 (11%).66

51. Rates of Conversion or Relapse Over 24 months CLRCHREFEP n8720545 Severe Psychosis 2.3%6.3% Relapse11% Negative Events* 22%25%40% * Hospitalizations, incarcerations, suicide attempts, assaults, rape

52. Psychotic Symptoms CHR vs. CLR = 0.0034 EFEP vs. CLR <0.0001

53. Negative Symptoms

54. Social Functioning

55. In school or working: Baseline and 24 months

56. Increases in participation in school, work or work and school from baseline to 24 months* * Odds Ratio, CHR+EFEP vs. CLR, = 3.44, 95% C.I. 1.16, 11.0, p=0.025

57. Global Test: Treatment vs. Control Overall outcomes over 24 months across ten clinical and functional variables Clinical High Risk Subsample Estimate S.E. t p 0.38 0.17 2.26 0.0244 EFEP Subsample t p 1.05 0.28 3.77 0.0002 Both Treatment Subsamples f p 7.50 0.0007

58. Outcomes in Four California PIER Programs* N = 125Baseline12 Month Working15% 49% In school57% 56% Onset of Psychosis:21% 3% Hospitalizations:13% 7% Suicide attempts:8% 2% *San Diego, Santa Clara (San Jose), Ventura Counties

59. Prediction of Psychosis Onset C=.79

60. Conclusions Community-wide education is feasible in 10 US cities. Referrals were 30% up to 60% of the at-risk population. Global outcome in FACT was better than regular treatment. The 2-year conversion rate for CHR is 1/5 of expected. The 2-year relapse rate for FEP is 1/4 of expected. Average functioning was in the normal range by 24 months. >80% were in school or working at 2 years. ¾ were in school or working up to 10 years later. Five cities show a declining incidence. Four county-wide California programs are replicating.

61. Conclusions Most mental health services in most communities in the United States can now begin to prevent onset of the initial psychosis in youth and young adults. We have the tools. The health, social and economic benefits are very substantial.

62. For further information: www.piertraining.com PTI@maine.rr.com mcfarw@mmc.org